Project Summary This proposal aims to determine mechanisms by which the neuroprotective hormone 17?-estradiol (E2) improves and maintains hippocampal synaptic signaling during presymtomatic Alzheimer?s disease (AD) pathology using the novel comprehensive TgF344-AD rat model. The earliest and most insidious stages of Alzheimer?s disease (AD) are characterized by altered brain function at the level of the synapse. Patholgoy begins in the entorhinal cortex (EC) and spreads via functionally connected synapse to the hippocampus. Both brain regions are critical to learning and memory. As soluble toxic species of amyloid beta oligomers and hyper-phosphorylated tau rise, EC-to- hippocampal synaptic weakening results and occurs decades prior to clinical presentation of cognitive symptoms. Ovarian hormones play a delicate role in modulating synaptic circuits and cognitive function. Rapid loss of ovarian hormones as a natural part aging in women is now recognized as a risk factor for the development of AD. 17?-estradiol (E2) and its replacement post-menopause benefits neuron function, amyloid and tau pathology, and cognition, yet how E2 improves or maintains synaptic processes underlying cognitive function throughout early asymptomatic and symptomatic disease progression are unknown. Our lab has established that E2-enhanced hippocampal synaptic strength and cognitive performance, in non- diseased rodents, is due to its ability to increase synaptic current mediated by glutamate receptor subunit epsilon- 2 (GluN2B) ?containing N-methyl D-aspartate receptors (NMDARs). Current evidence in presymptomatic transgenic rodent models show early hippocampal synaptic deficits result from loss of beneficial synaptic GluN2B-NMDARs transmission, while extrasynaptically located GluN2B-NMDARs are pathologically stimulated due to excessive extracellular glutamate. The current proposal will test the hypothesis that E2 is beneficial to synaptic function in early AD by enhancing synaptic GluN2B-NMDAR current and synaptic strength in the dentate gyrus, the primary target region of synaptic projections from EC. Data obtained in this proposal will bolster previous evidence of E2?s neuroprotective actions against Alzheimer?s disease pathology as well as establish novel therapeutic avenues.